A quantitative description of the energetics of nucleic acid structure, conformations and interactions is prerequisite for a detailed understanding of the biological function of DNA and RNA. In this proposal, I plan to carry out systematic measurements of the changes in volume accompanying fundamental physical processes in nucleic acids, including base pairing, ion and ligand binding, and correlate these values with heats and entropies determined on the same samples to provide a complete set of thermodynamic parameters for base-pairing of chains containing any sequence of complementary bases and for sequence specific drug binding interactions. The role of hydration in these processes is assumed to be important, but no such systematic values have been reported. Effects of mismatches, nicks, as well as conformational variations, including bends, hairpin loops, bulges and branches will be included. Parameters will be determined from complete thermodynamic profiles measured on sets of oligonucleotides of appropriate sequence and structure, using a combination of densimetric, calorimetric and spectroscopic techniques. Comparisons of the centered values between deoxy and ribo oligomers of similar sequence will be used to try to understand the differences in thermodynamics of DNA and RNA. Combined densimetry, calorimetry and spectroscopy will also be used to define the thermodynamics of netropsin, distamycin A and actinomycin D binding to oligonucleotides containing single binding sites. A high sensitivity magnetic suspension densimeter will be constructed following the design of Kupke, and used to make these measurements.